SEPTEMBER 2020

In this month’s Leukemia Insights newsletter, written by Prithviraj Bose, MD, and Srdan Verstovsek, PhD, MD, and sponsored in part by the Charif Souki Cancer Research Fund, ABOUT MyMDAnderson we summarize the investigational approaches available for patients with myeloproliferative neoplasms (MPN) at MD Anderson Cancer Center. Learn more about myMDAnderson is a secure, our Leukemia Program. personalized web site helping community physicians expedite patient referrals, as well as improve continuity Entering a New Era in Myeloproliferative of care through information access and streamlined communications. Neoplasms (MPN) Research with Multiple Physicians who have referred patients Phase 3 and Other Pivotal Clinical Trials to MD Anderson or plan to do so, can utilize the HIPAA compliant features Myelofibrosis: frontline studies of myMDAnderson to:

1. PACIFICA (NCT03165734): Pacritinib is a relatively non- • Refer a patient myelosuppressive JAK2/IRAK1/FLT3 inhibitor that may be particularly • View your patient's appointments effective in myelofibrosis patients with a “myelodepletive” phenotype. Access patient reports This oral agent is being specifically studied in patients with • Send and receive secure <50,000/µL platelets at baseline, who have a dismal prognosis and for messages whom no guidance on dosing is available for either ruxolitinib or fedratinib. This phase 3 trial enrolls JAK inhibitor-naïve patients as well as those with a limited exposure to ruxolitinib and randomizes JOIN THE COVERSATION them 2:1 to receive pacritinib or physician’s choice therapy, (low dose Connect with us. ruxolitinib, danazol, or corticosteroids). This trial is currently recruiting participants at MD Anderson. 2. MANIFEST-2: Bromodomain and extra-terminal (BET) inhibitors synergize with JAK inhibitors in myelofibrosis models. Following encouraging efficacy seen in the MANIFEST trial in JAK inhibitor- naïve patients (63% spleen response rate and 59% symptom response rate at 24 weeks), the combination of ruxolitinib and the oral BET inhibitor CPI-0610 will be compared to ruxolitinib plus placebo in JOIN OUR MAILING LIST this pivotal phase 3 trial. 3. TRANSFORM-1 (NCT04472598): Navitoclax, the predecessor of If you would like to receive venetoclax, inhibits both the anti-apoptotic proteins Bcl-2 and Bcl-xL. an electronic issue of the Bcl-xL may be particularly important for malignant cell survival in the MD Anderson Leukemia Insights context of JAK2 V617F, and synergism between ruxolitinib and e-Newsletter on a monthly navitoclax has been demonstrated in preclinical models of basis, please complete the myelofibrosis. Based on promising results achieved with the addition Subscription Request Form. of navitoclax in patients with a “sub-optimal” response to ruxolitinib (see below), this phase 3 trial will compare the combination of It's the easiest way to stay current ruxolitinib and navitoclax to ruxolitinib plus placebo in JAK inhibitor- with information on the latest leukemia news, research, and naïve patients with myelofibrosis. This study will open soon at MD resources. View archived issues. Anderson. 4. Ruxolitinib plus thalidomide (NCT03069326): Thalidomide has long been known to be clinically active in myelofibrosis and low dose thalidomide (50 mg/d), in particular, is well-tolerated and can improve CONTACT OUR STAFF cytopenias. Apart from being a poor prognostic marker in myelofibrosis, severe thrombocytopenia poses a significant clinical Mary Alma Welch - Editor Lisa Palacios - Publishing Editor challenge in everyday practice. In the first part of this phase 2 study, [email protected] encouraging platelet responses were seen in a Myelofibrosis: ruxolitinib failure number of patients (Rampal, ASH 2019). The second part of the study, soon to open at MD 1. MANIFEST (NCT02158858): BET inhibition down- Anderson, will restrict eligibility to patients with regulates many oncoproteins of interest in the baseline platelets <100,000/µL and both ruxolitinib MPNs, e.g., NF-kappa B, c-Myc and Bcl-2 family and thalidomide will be provided free of cost to members. This ongoing phase 2 study also has a participants. monotherapy arm in which CPI-0610 is administered alone in patients who are no longer Myelofibrosis: add-on studies on ruxolitinib. The results thus far have been promising with benefit seen in terms of spleen, 1. MANIFEST (NCT02158858): As noted above, dual symptom as well as anemia responses (Talpaz, inhibition of BET proteins and JAK2 has been EHA 2020). Accrual to this arm of the study found to be synergistic in MPN models. In the add- continues at MD Anderson. on arm of the phase 2 MANIFEST study, CPI-0610, 2. KRT-232 (NCT03662126): As noted above, there when added in patients with a sub-optimal exists a strong biologic rationale to test MDM2 response to ruxolitinib, produced encouraging inhibition as a therapeutic strategy in myelofibrosis. spleen and symptom responses, particularly in In the first results from this ongoing phase 2 study patients who were transfusion-dependent, a (Al-Ali, EHA 2020), a best spleen response rate of number of whom also achieved transfusion 16% was observed in patients with myelofibrosis independence (Verstovsek, EHA 2020). This cohort with disease that had relapsed after or was has, therefore, been expanded, and continues to refractory to ruxolitinib. This trial is continuing to accrue patients at MD Anderson. recruit patients at MD Anderson, and is expected to 2. Navitoclax (NCT03222609): JAK2 V617F be amended into a phase 3 trial. activates Bcl-xL and the combination of ruxolitinib 3. FREEDOM (NCT03755518): Although the oral and navitoclax is synergistic in preclinical models JAK2 inhibitor fedratinib is FDA-approved for the of JAK2 V617F-driven MPN. Promising clinical treatment of myelofibrosis, experience in the efficacy in terms of spleen and symptom responses setting of ruxolitinib failure is limited (a spleen has been observed in this ongoing phase 2 trial in response rate of 30% and a symptom response the add-on setting (Harrison, EHA 2020). This trial rate of 27% have been reported). FREEDOM is a is open to accrual at MD Anderson. single-arm, open-label, phase 3b study of 3. KRT-232 (NCT04485260): JAK2 V617F and fedratinib, 400 mg daily, in patients who are transforming growth factor beta (TGF-β) lead to resistant to or intolerant of ruxolitinib. Concomitant overexpression of MDM2, the physiologic luspatercept is available for anemic patients. This antagonist of p53, in myelofibrosis. TP53 mutations trial is open to accrual at MD Anderson. are rare in chronic phase myelofibrosis, making 4. MOMENTUM (NCT04173494): The oral JAK1/2 MDM2 inhibition an attractive therapeutic strategy. inhibitor momelotinib may improve anemia via The oral MDM2 inhibitor KRT-232 is active in inhibition of ACVR1/ALK2, thereby suppressing patients with JAK inhibitor-relapsed/refractory hepatic hepcidin production. MOMENTUM is a myelofibrosis (see below) and will now be studied randomized (2:1), phase 3 trial of momelotinib in the add-on setting in patients with a sub-optimal versus danazol in symptomatic, anemic patients response to ruxolitinib. This phase 1/2 trial is open with myelofibrosis who have previously failed an to accrual at MD Anderson. approved JAK inhibitor. This trial will open soon to 4. PU-H71 (NCT03935555): PU-H71 is an orally accrual at MD Anderson. administered inhibitor of the chaperone protein, 5. Pelcitoclax (NCT04354727): Pelcitoclax is a Bcl- heat shock protein 90 (HSP90). HSP90 inhibition 2/Bcl-xL inhibitor administered IV once weekly. can degrade JAK2, thus circumventing resistance This phase 1/2 trial enrolls patients who have to JAK2 inhibitors. This agent is being studied in a previously received ruxolitinib or fedratinib, and phase 1 add-on trial in patients with a sub-optimal were intolerant of, resistant/refractory to or lost response to ruxolitinib. This trial is open to accrual response to the same. Patients with a sub-optimal at MD Anderson. response to ruxolitinib may also enroll. This trial will 5. Ruxolitinib plus thalidomide (NCT03069326): open soon at MD Anderson. Apart from JAK inhibitor-naïve patients as 6. PRT-543 (NCT03886831): A novel epigenetic discussed above, this phase 2 trial also accrues target of interest in the MPNs is the arginine patients with myelofibrosis who have been on methyltransferase, PRMT5. PRT-543 is an oral ruxolitinib for at least 12 weeks and have not inhibitor of PRMT5 that is being studied in a phase achieved a complete or partial response. As noted 1 trial in patients with advanced solid tumors or above, the second part of the study restricts hematologic malignancies, including myelofibrosis. eligibility to patients with baseline platelets This study is open to accrual at MD Anderson. <100,000/µL and provides free ruxolitinib and thalidomide to patients. Myelofibrosis: anemia Ropeginterferon alfa-2b for hydroxyurea- resistant/intolerant essential thrombocythemia (ET) 1. Activin receptor ligand traps: This novel class of fusion proteins ameliorates anemia of diverse Ropeginterferon alfa-2b is a novel, monopegylated etiologies by sequestering ligands of the TGF-β interferon formulation approved in Europe for the superfamily that bind to the activin receptor to treatment of patients with PV without symptomatic suppress terminal erythroid differentiation. splenomegaly. It is administered subcutaneously, Encouraging activity was reported in an ongoing initially every 2 weeks and eventually every 4 weeks. MD Anderson phase 2 study of sotatercept This pivotal phase 3 trial (NCT04285086) is comparing (NCT01712308) for anemia of myelofibrosis, both ropeginterferon alfa-2b to anagrelide in patients with when used alone and in conjunction with ruxolitinib ET that is resistant to or intolerant of hydroxyurea. This (Bose, EHA 2019). Luspatercept, recently trial will open soon at MD Anderson. approved for the treatment of anemia in beta- thalassemia and myelodysplastic syndrome with Avapritinib for patients with advanced systemic ring sideroblasts, was studied for anemia of mastocytosis (PATHFINDER) myelofibrosis in a phase 2 trial (NCT03194542) with promising results, particularly in transfusion- Avapritinib is a highly potent and selective inhibitor of dependent patients receiving ruxolitinib (Gerds, mutant KIT recently approved for the treatment of ASH 2019). This cohort of the trial has since been PDGFRA-mutated gastrointestinal stromal tumor. The expanded, and is recruiting patients at MD KIT D816V mutation drives the vast majority of cases Anderson. A phase 3 study, INDEPENDENCE, of of systemic mastocytosis (SM). In the phase 1 luspatercept in this population, is also forthcoming. EXPLORER trial, an overall response rate of 77% was 2. INCB000928 (NCT04455841): This is an oral reported, and median overall survival was not reached ACVR1/ALK2 inhibitor that is being studied, both for any of the 3 subtypes of advanced SM, i.e., alone and in combination with ruxolitinib, in anemic aggressive SM (ASM), SM with an associated patients with myelofibrosis in a phase 1/2 trial that hematologic neoplasm (SM-AHN) and mast cell will soon open to accrual at MD Anderson. leukemia (Gotlib, EHA 2020). Avapritinib at a dose of 200 mg orally daily is now being studied in the Elotuzumab for patients with myelofibrosis not confirmatory phase 2 PATHFINDER trial candidates for JAK inhibitor therapy (NCT03580655). This trial is open to accrual at MD Anderson. Work from MD Anderson and Japanese investigators has shown that the fibrocytes that lead to bone marrow Pemigatinib for FGFR1 (8p11)-rearranged fibrosis in myelofibrosis are derived from monocytes myeloid/lymphoid neoplasms (FIGHT-203) which express SLAMF7. Elotuzumab is a SLAMF7- targeting monoclonal antibody approved for multiple Myeloid/lymphoid neoplasms with FGFR1 (8p11) myeloma. This phase 2 study (NCT04517851) enrolls rearrangement are an extremely rare and aggressive patients with JAK2-mutated myelofibrosis who are not group of malignancies with a poor prognosis. candidates for JAK inhibitor therapy (e.g., due to Pemigatinib is an oral inhibitor of fibroblast growth cytopenias/lack of splenomegaly or symptoms). factor receptors (FGFR) recently approved for the treatment of FGFR2-rearranged cholangiocarcinoma. PTG-300 (hepcidin mimetic) for phlebotomy- FIGHT-203 (NCT03011372) is an ongoing, pivotal requiring polycythemia vera (PV) phase 2 trial of pemigatinib for FGFR1 (8p11)- rearranged myeloid/lymphoid neoplasms. In Polycythemia vera is characterized by iron deficiency, preliminary findings from this study, an overall which is exacerbated by phlebotomy. PTG-300 is a response rate of 85% was reported (Verstovsek, ASH hepcidin mimetic that is administered subcutaneously 2018). This trial is recruiting patients at MD Anderson. once a week. To be eligible for this ongoing phase 2 trial (NCT04057040), patients must be phlebotomy- requiring. Concomitant cytoreductive therapy is permitted, but not required. The goals are elimination of the need for phlebotomy and correction of iron deficiency. This trial is open to accrual at MD Anderson. Announcements Leukemia Insights Newsletter

Our Leukemia Insights e-newsletter is now available online. Started in 2007 by Hagop Kantarjian, M.D., Leukemia Insights focuses on our various therapy options at MD Anderson Cancer Center. Click here to visit our new website.

Emil J Freireich Hematology Grand Rounds

The MD Anderson Cancer Center Emil J Freireich Hematology Grand Rounds now has a virtual format. This series highlights the incredible research taking place at MD Anderson Cancer Center while showcasing leaders from our research community, in an effort to remain engaged and inspired during the COVID-19 pandemic. Hosted by the Department of Leukemia in collaboration with the Department of Lymphoma/Myeloma, and Department of Stem Cell Transplantation and Cellular Therapy, we aim to strengthen the connections between the scientific and medical community at MD Anderson Cancer Center, our colleagues, patients and friends from around the world. Click here to visit our new website.

Leukemia Faculty Contacts Completing these studies in a timely manner will allow us to move quickly on positive leads. We appreciate referrals and will make every effort, once a patient is enrolled on a study, to continue as much of the care as possible through the referring oncologist. We also will keep you apprised of the patient's progress. View our faculty roster.

Clinical Faculty

Kantarjian, Hagop Department Chair (713) 792-7026

Garcia-Manero, Guillermo Deputy Chair, Chief, Section of Translational (713) 745-3428 Research, Chief, Section of Myelodysplastic Syndromes (MDS), and Director, Leukemia Clinical Fellowship Program

Konopleva, Marina Deputy Chair, and Chief, Section of Leukemia (713) 794-1628 Biology Research

Wierda, William Deputy Chair, Chief, Section of Chronic Lymphocytic (713) 745-0428 Leukemia (CLL), and Leukemia Center Medical Director

Andreeff, Michael Chief, Section of Molecular Hematology and Therapy, (713) 792-7261 Center Medical Director, Bone Marrow Aspiration Clinic

Borthakur, Gautam Chief, Section of Developmental Therapeutics (713) 563-1586

Daver, Naval Director, Leukemia Research Alliance Program (713) 794-4392

DiNardo, Courtney D. Co-Leader, Section of Acute Myeloid Leukemia (AML), (734) 358-1053 Co-Leader, Section of Developmental Therapeutics Leader, Hereditary Hematologic Malignancy Clinic

Ferrajoli, Alessandra Leukemia Center Associate Medical Director (713) 792-2063

Issa, Ghayas “Gus" Co-Leader, Section of Chronic Myeloid Leukemia (CML) (713) 745-8432

Jabbour, Elias Chief, Section of Acute Lymphoblastic Leukemia (ALL) (713) 792-4764

© 2020 The University of Texas MD Anderson Cancer Center Leukemia Faculty Contacts (Continued) Kadia, Tapan Co-Leader, Section of Acute Myeloid Leukemia (AML), (713) 563-3534 Co-Leader, Section of Developmental Therapeutics, Co-Leader, Leukemia Clinical Fellowship Program

Montalban Bravo, Guillermo Director, Chronic Myelomonocytic Leukemia (CMML) (713) 792-4956 Program

Pemmaraju, Naveen Director, Blastic Plasmacytoid Dendritic Cell Neoplasm (713) 794-3604 (BPDCN) Program

Ravandi, Farhad Chief, Section of Acute Myeloid Leukemia (AML) (281) 216-7806

Sasaki, Koji Co-Leader, Section of Chronic Myeloid Leukemia (CML) (713) 745-2882

Verstovsek, Srdan Chief, Section of Myeloproliferative Neoplasms (MPNs), (713) 745-3429 Director, Clinical Research Center for MPNs

Clinical Faculty Research Faculty

Alvarado, Yesid (713) 794-4364 Battula, Venkata (713) 563-2227 Bose, Prithviraj (713) 792-7747 Bhalla, Kapil N. (713) 563-8619 Burger, Jan (713) 563-1487 Burks, Jared K. (713) 792-7640 Chien, Kelly (713) 745-7584 Carter, Bing Z. (713) 794-4014 Estrov, Zeev (713) 794-1675 Chang, Kyung Hee (713) 792-4694 Jain, Nitin (713) 745-6080 Colla, Simona (713) 794-5223 Kornblau, Steven (713) 794-1568 Fiskus, Warren (713) 563-5901 Masarova, Lucia (832) 750-4211 Freireich, Emil (713) 792-2660 Montalban Bravo, Guillermo (713) 794-3604 Gandhi, Varsha V. (713) 792-2989 Ohanian, Maro (713) 792-0091 Han, Lina (713) 792-7640 Pemmaraju, Naveen (713) 792-4956 Ishizawa, Jo (713) 792-7640 Short, Nicholas (713) 563-4485 Keating, Michael (713) 745-2376 Takahashi, Koichi (713) 745-4613 Piya, Sujan (713) 792-7305 Thompson, Philip (713) 792-7430 Plunkett, William (713) 792-3335 Yilmaz, Musa (713) 745-9945 Post, Sean (713) 794-1458 Pourebrahimabadi, Rasoul (713) 792-7305 Rytting, Michael E. (713) 792-4855 Ruvolo, Peter (713) 745-9211 Wei, Yue (713) 792-9854 Yang, Hui (713) 792-2558 Zhang, Weiguo (713) 794-4085

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